This invention relates to a novel process and intermediates for preparing a methoxytrifluoromethylnaphthoic acid compound of formula ##STR3## from 1-methyl-5-naphthoic acid. The methoxytrifluoromethylnaphthoic acid of the present invention, which is designated as 2-methoxy-1-trifluoromethyl-5-napthoic acid, is useful as a chemical intermediate for the synthesis of various end-products. In particular, one such end-product is a therapeutic agent having efficacy for inhibiting aldose reductase activity in human tissues. This compound, which is a naphthyl thioamide compound of formula ##STR4## is currently being evaluated for such efficacy. This is a proprietary compound of the Ayerst Research Laboratories and is designated by the trademark Tolrestat. Tolrestat is believed to inhibit the aldose reductase enzyme in human cells which converts glucose into sorbitol. Excessive sorbitol production in humans is a condition common to a large number of diabetics, and has been linked to chronic complications among diabetics such as blindness, hypertension, pain and discomfort. See Chemical & Engineering News, page 5 (Sept. 5, 1983).
The cost of Tolrestat is presently quite high due in part to the high cost of the raw materials used in manufacturing this drug. One of the primary raw materials is the methoxytrifluoromethylnaphthoic acid of the present invention.
Various methods are disclosed in the prior art for preparing 2-methoxy-1-trifluoromethyl-5-naphthoic acid. Thus, it is known to react a mixture of iodine and iodic acid with 6-methoxy-1-naphthalenecarboxylic acid methyl ester in a mixture of acetic acid and sulfuric acid to prepare 5-iodo-6-methoxy-1-naphthalenecarboxylic acid methyl ester. This compound can then be reacted with trifluoromethyl iodide in pyridine in the presence of copper powder and subsequently hydrolyzed in a mixture of sodium hydroxide and methanol to prepare 2-methoxy-1-trifluoromethyl-5-naphthoic acid. Alternatively, the 5-iodo-6-methoxy-1-naphthalenecarboxylic acid methyl ester can be reacted with a mixture of copper, mercuric thiofluoride, and cuprous thiomethyltrifluoride (CuSCF.sub.3) in dimethylformamide, and subsequently hydrolyzed in a mixture of 2-methoxyethanol and sodium hydroxide to prepare the target compound. These procedures are described in more detail in examples 1f, 1h and 63 of European Patent Application No. 59,596, published Sept. 8, 1982.
Fung et al in the Canadian Journal of Chemistry, Vol. 61, pp. 368-371 (1982) describe the preparation of 1-trifluoromethyl-2-naphthalenols from 3-chloropropyltoluene. The 3-chloropropyltoluene is reacted with magnesium, a catalytic amount of iodine and a suspension of lithium trifluoroacetate in anhydrous ether to prepare the corresponding ketone. The ketone is then used to prepare a ketone-oxime by reaction with potassium nitrate in water and acetic acid. The ketone-oxime is then reacted with concentrated sulfuric acid to close the ring, and subsequently hydrolyzed with concentrated hydrochloric acid to prepare the hydroxyketone. The hydroxyketone is dehydrated by reaction with thionyl chloride, 4-dimethylaminopyridine and pyridine, and subsequently methylated with dimethylsulfate to prepare 2-methoxy-5-methyl-1-trifluoromethylnaphthalene, the methyl analog of the carboxylic acid compound of the present invention.
As is evident from the foregoing, prior art processes for preparing methoxytrifluoromethylnaphthoic acid or analogous compounds suffer from numerous disadvantages. These processes are cumbersome, involve expensive reactants and/or reagents and processing techniques, and are not readily adaptable for commercial production. It will be readily apparent to those skilled in the art, therefor, that a need exists to develop an improved process for preparing methoxytrifluoromethylnaphthoic acid using readily available and inexpensive raw materials and commercially feasible processing techniques. One such process utilizing 1,5-dimethylnaphthalene as a starting material is disclosed in a commonly assigned copending application filed of even date herewith. The present application is directed to an alternate process utilizing 1-methyl-5-naphthoic acid as a starting material.